ARIAD Pharmaceuticals, Inc., a biopharmaceutical company, and Newcastle University, on behalf of the UK National Cancer Research Institute, or NCRI, CML Working Group, have announced an agreement to collaborate on a multicenter, randomized Phase III trial, named SPIRIT 3, to assess the impact of switching patients with chronic myeloid leukemia, or CML, being treated with a first-line tyrosine kinase inhibitor, upon suboptimal response or treatment failure, to ponatinib.
The NCRI expects to begin enrollment in the trial of 1,000 patients at approximately 172 clinical research sites in the UK in the second quarter of 2013.
The SPIRIT 3 trial is a randomized, two-arm, multicenter trial that compares major molecular response (MMR) at three years in newly diagnosed patients treated with imatinib to those treated with nilotinib, when patients are rescued with ponatinib upon suboptimal response at three or 12 months or treatment failure. The SPIRIT 3 trial will enroll adult patients with chronic-phase CML diagnosed within three months and previously untreated for CML with any TKI therapy.
Approximately 1,000 patients will be randomized 1:1 to standard doses of imatinib (400 mg orally once daily) or nilotinib (300 mg orally twice daily). Patients will be switched to ponatinib (45 mg orally once daily) based on defined criteria of suboptimal response, treatment failure, or intolerance to first-line therapy.
The primary endpoint of the study is the proportion of patients who have achieved MMR at three years on their initially allocated first line of therapy, regardless of switch to ponatinib. MMR is defined as a less than or equal to 0.1% ratio of BCR-ABL to ABL transcripts on the International Scale measured in peripheral blood by PCR testing.
The sample size of 500 patients per arm in the SPIRIT 3 protocol provides over 90 percent power to show non inferiority in three-year MMR rates between patients starting on imatinib, allowing switch to ponatinib, and patients starting on nilotinib, allowing switch to ponatinib. These sample size calculations use a noninferiority margin of a 10 percent absolute difference and assume a 73 percent MMR rate at three years in each arm.
Secondary endpoints include the proportion of patients who have achieved therapy cessation three years from having achieved stable MMR, cost of therapy (measured as incremental cost per quality adjusted life year gained), overall survival, progression-free survival, event-free survival, and treatment failure rates at five years, as well as safety and tolerability of the TKIs. Each patient will be followed for a minimum of five years from the time the last patient in the trial is randomized to either treatment arm.
A key feature of the trial is that patients achieving stable MMR will be offered the opportunity to reduce the dose of their TKI therapy or stop treatment altogether. These patients will be monitored more closely with monthly PCR testing and will be reverted back to full-dose TKI therapy for loss of MMR at any time or rising BCR-ABL transcript ratio on two consecutive tests.
Iclusig is a kinase inhibitor. The primary target for Iclusig is BCR-ABL, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia (CML) and Philadelphia-chromosome positive acute lymphoblastic leukemia (Ph+ ALL). Iclusig was designed using ARIAD's computational and structure-based drug design platform specifically to inhibit the activity of BCR-ABL.
"The SPIRIT 3 study was designed in partnership with ARIAD to provide the scientific community and patients living with chronic-phase CML a deeper understanding of the most effective ways to use TKIs and whether we can improve treatment outcomes by switching patients to ponatinib, who have failed to achieve optimal response from imatinib or nilotinib," stated Stephen O'Brien, Professor of Hematology at the Northern Institute for Cancer Research at Newcastle University, NCRI member and chief investigator of the SPIRIT 3 study. "We look forward to assessing ponatinib as a treatment in this setting and evaluating its potential clinical, economic and quality-of-life benefits."
"We are deeply committed to helping physicians and CML patients improve outcomes with TKI therapy," stated Frank Haluska, chief medical officer at ARIAD. "The SPIRIT 3 trial will evaluate the potential for ponatinib to improve outcomes in patients who have sub-optimal responses early in the course of first-line therapy for CML, by enabling those patients with a poorer prognosis to switch TKI therapy. This should have important implications for the future management of CML."